The immune system, composed of cells of the bone marrow, spleen, and hematopoietic cells, including but not limited to lymphoid and myeloid lineage cells, is responsible for defending against bacteria, viruses, and foreign multicellular organisms, as well as cancer cells. Improper regulation of the immune system can result in a number of disorders or pathological conditions, e.g., chronic inflammation, autoimmune diseases and disorders, and undesired allergic reactions to foreign particles or foreign tissues.
Mast cells, a myeloid lineage immune cell, secrete a variety of cytokines and enzymes that result in inflammation. As some of these substances occur in secretory vesicles that appear granular, the process of secretion is sometimes called degranulation. Rapid degranulation by mast cells contributes to the pathology of asthma, anaphylaxis, and other allergic responses, while slower degranulation by mast cells contributes to arthritis and other types of chronic inflammation. The release of inflammatory cytokines and enzymes by mast cells can result in tissue damage, further attraction of mast cells, resulting in further tissue damage.
Cells of the immune system possess many types of membrane-bound proteins that can serve as receptors. The ligands for these receptors can be small molecules, proteins, e.g. cytokines or chemokines, or membrane-bound proteins residing on a separate cell. Changes in the activity of a cell or tissue can result from occupation of a receptor by its physiological ligand, by an analogue of the physiological ligand, by an antibody, by agents that cross-link like-receptors to each other, and by agents that cross-link non-identical receptors to each other.
Mast cells contain a number of receptors that relay an inhibitory signal to the dell. These include CD200 receptor a (a.k.a. CD200Ra; OX2Ra), as well as various Ig-ITIM-bearing receptors, e.g., low affinity IgG receptor FcγRIIB, transmembrane glycoprotein receptor gp49B1, signal regulatory protein (SIRP), mast cell function-associated Ag, and platelet endothelial cell adhesion molecule-1 (PECAM-1)/(CD31) (Wong, et al. (2002) J. Immunol. 168:6455-6462).
CD200 (a.k.a. OX2) is a widely distributed membrane-bound protein occurring on lymphoid, neuronal, endothelial, dendritic cells, and B cells (Wright et al. (2000) Immunity 13, 233-242; Wright, et al. (2001) Immunology 102:173-179; Hoek, et al. (2000) Science 290:1768-1771; Barclay, et al. (2001) Immunol. 102:173-179; McCaughan, et al. (1987) Immunogenetics 25:329-335). CD200, the ligand of CD200R, can bind to CD200R, which is expressed on a separate cell. In humans, two subtypes of CD200Rs have been identified, hCD200Ra (SEQ ID NO:2) and hCD200Rb (SEQ ID NO:4). Murine homologs of CD200R consist of four receptor subtypes, CD200Ra (SEQ ID NO:6), CD200Rb (SEQ ID NO:8), CD200Rc (SEQ ID NO:10), and CD200Rd (SEQ ID NO:12). CD200Ra occurs, e.g., on macrophages, dendritic cells, and microglia, of the rat (Wright, et al. (2000) supra; Preston, et al. (1997) Eur. J. Immunol. 27:1911-1918.
Several regulatory pathways involving the membrane bound proteins for various immune cells have been identified. However, the molecules responsible for mast cell regulation are poorly understood. The present invention fulfills this need by providing methods of diagnosis and treatment of mast cell disorders by targeting mast cell receptor molecules, e.g., CD200Rs.